1. Field of the Invention
The present invention relates to the use of acetylenes disubstituted with a phenyl or heteroaromatic group and a substituted chromanyl, thiochromanyl or tetrahydroquinolinyl group for the treatment of tumors in combination with other anti-tumor agents. More particularly the present invention relates to the use of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate for the treatment of malignancies, particularly carcinoma of the breast and human myeloid leukemia, in combination with interferons and other anti-tumor agents.
2. Background Art
Naturally occurring retinoic acid and related compounds, generally called retinoids, have been known in the pharmaceutical, medical and related arts to have of important biological activity, including prevention and inhibition of malignant cell proliferation. A vast volume of patent and scientific literature exists describing the synthesis of retinoid compounds, their biological activities and investigations aimed at discovering the varying modes of action of retinoids in human and other biological systems, in vitro and in vivo as well.
Specifically, it is generally accepted in the art that in the anti-cell-proliferative or anti-tumor field, pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful for treating or preventing hyperproliferative disorders of the skin, and other premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi's sarcoma. Still more specifically, there are published reports in the art that certain retinoid compounds act additively and some even synergistically with other known anti-tumor chemotherapeutic agents, such as interferons and other drugs, in several carcinoma of the breast cell cultures to suppress or inhibit the proliferation of the cancer cells. The publication by Fanjul et al. in Cancer Research 56, 1571-1577 (1996) describes assays of several retinoid compounds, including a compound designated in the publication as SRI 11220 in combination with interferon in several carcinoma cell lines, and states that in some of the cell lines the anti-proliferative activity of the compound SRI 11220 and interferon was synergistic. The structure of this prior art compound SRI 11220 is shown below. SRI 11220 (Prior Art)
A publication by Toma et al. in International Journal of Oncology 10: 597-607 (1997) describes synergistic effects of certain other retinoids, such as all trans retinoic acid (tRA) with a interferon (α IFN) and synergistic effect with other chemotherapeutic agents such as tamoxifen (TAM) in MCF-7 human breast cancer lines. As further background to the present invention it is noted that a publication by Kurbacher et al. in Cancer Letters 103 (1996) 183-189 describes synergistic action of vitamin C with certain chemotherapeutic anti-tumor agents in MCF-7 and MDA-MB 231 human carcinoma cell lines.
U.S. Pat. Nos. 4,810,804, 4,980,369, 5,045,551, and 5,089,509 describe acetylenes disubstituted with a phenyl or heteroaromatic group and a substituted chromanyl, thiochromanyl or tetrahydroquinolinyl group having retinoid like activity. U.S. Pat. Nos. 5,602,130 and 6,090,826 disclose a method of treating diseases or conditions susceptible to treatment by retinoids, with acetylenes disubstituted with a heteroaromatic group and a substituted chromanyl, thiochromanyl or tetrahydroquinolinyl group. U.S. Pat. No. 5,089,509 is of particular relevance as background to the present invention, because it discloses the synthesis of ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate which is the preferred compound used in the method of treatment of the present invention. Ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate is also known by its trade name TAZAROTENE®, and is often referred to in the present specification (including the drawing figures) simply as “tazarotene”.